The present invention regards a solid form of dry sucralfate gel in porous granular form, the process for its preparation, and pharmaceutical compositions that contain it either as active principle, or for pharmaceutical compositions comprising it as coating and other active principles that may cause lesions to the gastric mucosa.
Sucralfate is a drug for the treatment of ulcers for which a non-systemic mechanism of action has been proposed. In fact, its activity depends upon its capacity to bind to the ulcerated sites of the gastric mucosa, thus creating a physical barrier that is able to protect the mucosa from the aggression of acids and enzymes. This mechanism has stimulated pharmaceutical research workers to improve those characteristics of the product that have a direct influence on its capacity to exert an action of xe2x80x9cprotective coatingxe2x80x9d of the gastrointestinal wall. Particular attention has been directed to the granulometric characteristics and the specific surface area of the preparation, to its physical structure (crystallinity, structure of bound water, etc.) and to its reactivity with acids. Recently, this xe2x80x9cclassicxe2x80x9d mechanism of action has been enhanced by new experimental findings, which, without taking anything away from the need for sucralfate to interact with the gastrointestinal mucosa, have shown that also mechanisms linked to the activity of the PGE2 prostaglandins or of the Epidermal Growth Factor must be taken into account. More recently, significant light has been shed on the role that a micro-organism, Helicobacter pylori, plays in the development of pathological conditions involving gastric erosion. Many research workers are convinced that the reason for which the bacterium manages to settle in an environment which is decidedly hostile on account of the high gastric acidity, is to be sought in the capacity of the said bacterium to attach to the epithelial cells of the stomach, which are able to offer various binding sites. It may be inferred from this how important it is to be able to prevent the implantation of the bacterium by identifying a therapeutic means that is able to compete with the bacterium for the binding sites or to attack it with a specific action, such as localized antibiotic treatment. To achieve this, a therapeutic tool is needed that can bind to the mucosa, compete with the binding sites of the germ, and convey and keep in situ an antibacterial agent to which the germ is sensitive.
The European Patent EP 0286978 describes a physical form of sucralfate, referred to as xe2x80x9cgelxe2x80x9d on account of its peculiar colloidal characteristics. Sucralfate gel could take on the role of agent expressly designed to counteract Helicobacter pylori and its harmful consequences. In fact, this new gel form of sucralfate has proved to possess impressive bio-adhesive characteristics in regard to the gastric mucosa, its adhesive property being much higher than the one possessed by sucralfate in the powder form. This biophysical superiority has determined a higher anti-ulcer activity, so much so that the sucralfate gel form has made it possible to halve the therapeutic dose of sucralfate from 4 g/day to 2 g/day, with unquestionable advantages, also in terms of patient compliance.
From the technological point of view, this superior activity of sucralfate gel has been obtained thanks to an original process of production of the starting material. The active principle sucralfate is a complex salt of sucrose octasulphate with aluminium hydroxide, and the manufacturing process concludes with the precipitation of the salt from an aqueous solution of the two counter-ions, aluminium and sucrose octasulphate, with a subsequent drying phase that gives rise to an amorphous powder.
The innovation obtained with sucralfate gel is represented by the change in the physical properties, so as to obtain a colloidal form. This physical colloidal form, referred to as xe2x80x9cgelxe2x80x9d, is demonstrated not only by the granulometric properties, but above all by the thixotropic rheological characteristics of the aqueous suspension of sucralfate gel, which account for its high capacities of adhesion to the mucosae of the gastro-intestinal tract.
The rheological and bio-adhesive properties of sucralfate gel are lost when the precipitated gel is brought to the dry state by means of ordinary techniques of drying using heat or vacuum-drying. Consequently, the starting material sucralfate gel used for the preparation of the pharmaceutical forms consists of a moist solid that is simply the filtered precipitate containing a large quantity of water bound to the colloidal particles of sucralfate. Keeping the starting material in the dry state is a necessary condition and the only way for preserving the superior activity of sucralfate gel. This means that the pharmaceutical forms that can be prepared with the moist solid are only the aqueous suspensions.
This fact, however, poses strict limits on the pharmaceutical forms available for the therapy using sucralfate gel, in so far as it does not enable the preparation of solid pharmaceutical forms, such as tablets, capsules, tablets for chewing or powder. In fact, the current form of administration of sucralfate gel is necessarily an aqueous suspension which, even though it may be very suitable for the type of pathological condition and for the role that the product must perform, raises problems linked to the high volumes to be transported, possibilities of bacterial pollution, and impracticality of use.
The international patent application WO9605483 presents a spray-drying process for sucralfate gel developed starting from an aqueous suspension of sucralfate gel, in which an appropriate amount of a gel-protective agent was present, i.e., a compound provided with hydroxyl groups. The solid compound obtained from this drying technique, when re-dispersed in water, gave rise to a suspension that possessed the same characteristics as those of the starting products; namely, it presented gel properties.
Unfortunately, this method for drying sucralfate gel proved somewhat disadvantageous, in that it involved a long and laborious process that entailed mixing of mannitol in considerable quantities with sucralfate gel, long drying times with considerable expenditure of energy, and yields of around 50%. In addition, the spray-dried product obtained, which had dimensions of just a few micron, had to undergo further stages of treatment in order to arrive at a granulate suitable for the preparation of pharmaceutical forms, such as ordinary tablets of tablets for chewing.
Now we have found, and this constitutes the main subject of the present invention, a new form of granular and porous dry sucralfate gel, which is particularly suitable for the preparation of solid pharmaceutical forms that are able to preserve, once re-dispersed in water, the peculiar properties of a gel.
This sucralfate gel in solid form presents a particle-size distribution of between 100 and 1000 xcexcm, an apparent density of the powder bed of between 0.7 and 0.9 g/ml, a settling index, as defined by R. L. Carr in xe2x80x9cEvaluating flow properties of solidsxe2x80x9d, Chem. Eng. 72:163-168 (1965), of between 5 and 15%, and, finally, a residual humidity of between 5 and 15%.
A further subject of the present invention is the process of preparation of the above-mentioned solid form, which comprises the following steps:
a) A diluted aqueous dispersion is prepared, which presents a viscosity of between 10 and 20 mPa.s, of powdered sucralfate gel.
b) The diluted aqueous suspension obtained from step (a) is subjected to drying by treatment with microwaves.
This drying technique using microwaves makes it possible to overcome the numerous drawbacks linked to the spray-drying process described previously. Unlike the powdered sucralfate gel obtained using the spray-drying techniques, which is characterized by a very fine powder, the powdered sucralfate gel according to the present invention takes the form of a granular and porous solid product which, when brought into contact with water and simply stirred, gives rise to a homogenous suspension of sucralfate gel having the same thixotropic and bio-adhesive properties as the suspension of moist sucralfate gel. Furthermore, it is not necessary to add a gel-protective agent since, in the granular and porous dry sucralfate gel according to the present invention, the typical properties of moist sucralfate gel are maintained without the addition of the said substances in the drying phase, an operation which is instead indispensable in the case of sucralfate gel obtained by means of spray-drying.
Consequently, the dry sucralfate gel in the porous granular form, which is the subject of the present invention, when re-dispersed in water, gives rise to a suspension that possesses the same characteristics as those of the starting suspension; namely, it presents gel properties.
A further subject of the present invention is represented by pharmaceutical compositions in solid form for oral use containing as active principle the dry sucralfate gel in granular and porous form that is the subject of the present invention. The fact that the sucralfate gel according to the present invention comes in the form of an extremely porous granulate makes it particularly useful for conveniently preparing solid pharmaceutical forms, such as tablets that can be chewed, which re-disperse with surprising rapidity in an aqueous means, such as saliva.
A further subject of the present invention is represented by pharmaceutical compositions for oral use comprising:
i) a core containing an active principle which may cause lesions to the gastric mucosa;
ii) a coating of the said core which contains as main component the porous granular dry sucralfate gel that is the subject of the present invention.